Acute Respiratory Distress Syndrome (ARDS) continues as a predominant cause of death (mortality of 50-80%) in burn patients. Multiple ARDS trials have shown an improvement in survival with a Low Tidal Volume (LTV = 6 ml/kg) ventilator management strategy to reduce lung stretch. LTV, however, remains controversial and may cause alveolar hypoventilation, hypercapnia, and acidosis and may require higher levels of PEEP and FiO2. ArterioVenous Carbon Dioxide Removal (AVCO2R) utilizes a low-resistance gas exchanger in a simple percutaneous arteriovenous shunt of only 10-15% cardiac output to achieve extracorporeal removal of CO2 production. Our animal and patient trials show AVCO2R allows decreased respiratory rate, tidal volume, and peak airway pressures with no significant decrease in WBC, platelets, or activation of complement while maintaining CO2 and pH homeostasis. We have also shown high frequency percussive ventilation (HFPV) significantly decreases lung stretch and potentially improves survival in smoke/bum injured sheep. We will test our hypothesis that ARDS caused by a smoke/bum injury is best treated with gentle pulmonary or extracorporeal gas exchange to reduce lung stretch, to ameliorate the pathophysiology of ARDS, and achieve respiratory support and promote lung recovery. Specifically, using our clinically relevant, LD100 sheep model of smoke/bum induced ARDS in three-arm prospective randomized trials we will: 1) determine ventilator free days (VFD) and survival of the three gentle ventilation techniques (AVCO2R, HFPV and LTV) in a 10-day outcomes study, and 2) evaluate pathophysiology of AVCO2R, HFPV and LTV at 48 and 72 hours by comparing: IL-8 protein, in lung lymph and tissue, poly (ADP-ribose) polymerase activity, MAPK including JNK/SAPK, p38 and ERK1,2 kinase activity in lung tissue and in bronchial epithelium, and estimate peroxynitrate formation in lung parenchyma. PMN flux into the airway will be estimated from PMNs in lung lymph and airway PMNs from bronchoalveolar lavages. A Zeiss confocal microscope (LSM 510 UV META) will quantitate MAPKs and other molecules in single cells from lung tissue sections from the three different ventilation techniques. Bronchial epithelium and basal cells will be removed mechanically from bronchi for measurement of the same MAPK by Western blotting. Knowledge gained from these clinically pertinent large animal studies will provide insight into CO2 homeostasis and lung stretch on the pathophysiology of ARDS and determine the optimal ventilator management strategy for treatment of ARDS.